1. Field of the Invention
The invention relates to drug delivery systems and more particularly to lipidic delivery systems that increase circulation time yet rapidly degrade at reduced pH. The novel lipid derivatives in this invention and the lipidic delivery systems that contain them rapidly degrade in the pH range from 4.0 to 6.0. The lipid derivatives can be used to modify the delivery properties of the lipidic delivery systems to enable prolonged circulation times or more rapid drug unloading in the target tissue.
2. Description of the Related Art
There are a number of important classes of amphipathic molecules that contain both a polar head group and a large hydrophobic moiety. In aqueous phase, such molecules self-assemble into colloidal particles such as liposomes, micelles and hexagonal phase. Liposomes are widely used as models of membrane bilayers and carriers of a variety of diagnostics and medicines. Examples of their use in drug delivery include PEG stabilized liposomes that carry cytotoxic drugs to leaky tumor tissues and cationic liposomes that improve gene transfection.
Ideally, targeted drug delivery systems utilizing liposomes should remain stable until they reach the target site to minimize the premature loss of payload. Upon accumulation at the target site, drug release needs to be at a high enough level for an effective therapeutic response. Since the decrease of pH is implicated in many physiological and pathological progressions such as endosome processing, tumor growth, inflammation and myocardial ischemia, it has been extensively exploited to trigger the release of drugs from liposomal delivery systems in the past twenty years. Most of the reported pH sensitive liposomes are based on the neutralization of excess negative charges on their surface upon protonation, which reduces the hydrodynamic diameter of lipid head groups and triggers the change of lipid bilayers to hexagonal phases. However, at neutral pH, these excess negative charges induce undesired interactions with serum proteins and fixed macrophages, leading to rapid elimination of the liposomes from circulation. Efforts to circumvent this difficulty and provide a non-ionic pH sensitive lipid have employed a neutral monosaccharide as the head group, which is attached to long hydrophobic chains via an acetal moiety. However, these acetal analogs hydrolyze relatively slowly at pHs 5 to 7 as found in physiological environment and need a pH less than 4 for rapid degradation. Recently, a number of acid- and light-sensitive lipids containing vinyl ether moieties have been reported. Neverthelss, the rate of hydrolysis at pH 5 of these vinyl esters is not optimal for rapid drug release.
The pH-sensitive properties of the diortho ester moiety have been used by the prior art to develop sustained drug release systems. These systems rely on polymer chains of multiple ortho esters that degrade in multiple places.
Methods to enhance the circulation time by coating the liposome with polyethyleneglycol have been devised. This PEG coating works to extend the circulation time by shielding the liposome surface so that the liposomes do not appreciably interact with cells that remove liposomes from circulation. However, once the PEG-coated liposomes reach the target organ they do not interact with cells in this organ.
The efficiency of delivery remains as a key factor for the success of gene therapy. Cationic liposomes are the most intensively studied synthetic gene vectors with substantial success in vivo. However, most of the cationic lipoplexes are trapped in the endosomes following cellular uptake and finally processed to lysosomes, where they are degraded. In fact, viruses which infect their host cells via the endocytic pathway rely on specific proteins to destabilize endosome membranes so as to translocate the viral genomic DNA into the cytoplasm.
Thus, what has been needed is a delivery system that release its encapsulated material at a mildly acidic pH encountered in physiological or pathological scenario. There is a further need for compositions and drug delivery systems that lengthen circulation time while still providing effective release. An additional need is a drug delivery system optimized for receptor-mediated uptake. This invention satisfies these and other needs.